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Principal Investigator: Andrew Mehle
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $632,278
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Influenza virus is a serious public health threat causing high levels of morbidity and mortality. The annual disease
burden from influenza places a significant strain on our healthcare infrastructure and economy. This is despite
many efforts to control disease with yearly vaccination, antiviral drug therapies, and other medical and public
health interventions. To address the continuing health and economic costs, there is a clear need to better
understand the molecular mechanisms of influenza virus replication and how these can be manipulated for
therapeutic benefit. Influenza virus exploits, and in some cases subverts, cellular factors and pathways to
promote replication. We identified RNA:protein interactions between viral and host partners that impact innate
immune responses during infection. We showed IFIT2 is a critical cellular protein that binds viral mRNAs to
enhance replication. This was surprising, as IFIT2 is one of the first proteins expressed in response to viral
infection and displays broad-spectrum antiviral activity. The mechanisms underlying the antiviral activity of IFIT2,
and how this is co-opted into a proviral effector by influenza virus, are not yet known. We also showed that
influenza nucleoprotein (NP) is a key viral protein that binds host RNAs. This assigns a new activity to NP that
our data suggest is part of a previously unappreciated strategy to dampen innate immune responses. The overall
goal of this application is to determine how these RNA:protein complexes composed of both viral and host
components manipulate innate immune responses to support viral replication. In Aim 1, we investigate how IFIT2
functions as a front-line defender in a broadly acting antiviral response. We hypothesize that IFIT2 enhances
translation of antiviral proteins, an event that is repurposed by influenza virus to promote production of viral
proteins. We test this using experiments that investigate the processes by which IFIT2 engages target RNAs,
affects translation of its bound mRNAs, and alters infection. Aim 2 interrogates the impact of interactions between
viral NP and host RNAs. This aim proposes that NP:RNA complexes moderate innate immune responses. We
investigate this by studying RNAs and infection-induced events that activate innate immune pathways, and
discern the impact on viral replication. The results from this proposal will establish a mechanistic understanding
of the viral and host factors regulating innate immune responses and how influenza virus tips the balance to
favor replication. Moreover, while our studies focus on influenza virus, the underlying mechanisms we discover
will have broad impacts on the general understanding of host antiviral responses and unexpected strategies
used by viruses to counteract them. Completion of this proposal will provide fundamental knowledge that can
contribute to new therapeutic approaches or cellular targets that can be exploited for the rational development
of anti-influenza virus therapies.
Terms: <Address><Affect><Anti-viral Agents><Anti-viral Response><Binding><Binding Proteins><Cell Body><Cells><Complex><Data><Detection><Development><Drug Therapy><Environment><Equilibrium><Event><Goals><Grippe><Health Care Costs><Health Costs><Healthcare><Healthcare Costs><Host Factor><Host Factor Protein><IFN><Immune><Immune Cell Activation><Immunes><Impairment><Infection><Influenza><Influenza Virus><Infrastructure><Innate Immune Response><Integration Host Factors><Interferons><Invaded><Knowledge><Ligand Binding Protein><Ligand Binding Protein Gene><Medical><Messenger RNA><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><NIH><National Institutes of Health><Non-Polyadenylated RNA><Nucleic Acids><Nucleoproteins><Outcome><Pathway interactions><Pattern recognition receptor><Pharmacotherapy><Process><Production><Productivity><Protein Binding><Proteins><Public Health><RNA><RNA Gene Products><RNA amplification><RNA and protein interaction><RNA-Protein Interaction><Recurrence><Recurrent><Research><Ribonucleic Acid><Ribosomes><Role><Severities><Shapes><Strategic Planning><Testing><Therapeutic><Therapeutic Intervention><Translations><United States National Institutes of Health><Vaccination><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Gene Products><Viral Gene Proteins><Viral Physiology><Viral Proteins><Virus><Virus Diseases><Virus Replication><Work><anti-flu><anti-influenza><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiflu><balance><balance function><bound protein><burden of disease><burden of illness><cellular targeting><developmental><direct application><disease burden><disease control><disorder control><drug treatment><economic cost><experiment><experimental research><experimental study><experiments><flu infection><flu outbreak><flu virus infection><gene product><genetic association><health care><immune activation><immunogenic><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza outbreak><influenza virus infection><influenzavirus><innate immune pathways><insight><intervention therapy><mRNA><mortality><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><pan influenza vaccine><pan influenza viral vaccine><pan influenza virus vaccine><pandemic><pandemic disease><pathogen><pathway><prevent><preventing><protein complex><public health intervention><response><seasonal flu><seasonal influenza><sensor><social role><success><translation><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine against flu><universal vaccine against influenza><viral RNA><viral infection><viral multiplication><viral replication><virus RNA><virus infection><virus multiplication><virus protein><virus-induced disease>